Abstract Nicotine dependence is a prevalent and costly public health epidemic. While several treatment options exist, the majority of individuals who try to quit will eventually relapse even when using currently available cessation aids. Therefore, medications with novel mechanisms of action are needed to enhance cessation rates. For instance, converging preclinical evidence shows that orexin antagonism has substantial promise for treating addiction. This current R03 application will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to nicotine dependent smokers. Given that orexin antagonism blunts the motivation to attain abused substances in preclinical models, we hypothesize to find a similar effect in smokers. Specifically, suvorexant will be administered in a dose dependent manner using a double-blind, placebo controlled, cross over design. The impact of orexin antagonism on smoking cue- induced craving and the subjective effects of acute smoking will be tested. Given that both orexin and nicotine impact dopaminergic signaling, more general reward sensitivity also will be evaluated. Potential side effects related to suvorexant?s action as a sleep aid also will be measured. This work will offer key information on the role of orexin in nicotine dependence and will suggest whether orexin antagonists may be a viable treatment strategy for nicotine dependence. This R03 application will provide pilot and feasibility data necessary for larger projects that directly evaluate the neurobiological impact of orexin antagonism in nicotine dependent individuals.